NK cells are rapid IFN-gamma responders to Plasmodium falciparum-infected erythrocytes (PfRBC) in vitro and are involved in controlling early parasitaemia in murine models, yet little is known about their contribution to immune responses following malaria infection in humans. Here, we studied the dynamics of and requirements for in vitro NK responses to PfRBC in malaria-naive volunteers undergoing a single experimental malaria infection under highly controlled circumstances, and in naturally exposed individuals. NK-specific IFN-gamma responses to PfRBC following exposure resembled an immunological recall pattern and were tightly correlated with T-cell responses. However, although PBMC depleted of CD56(+) cells retained 20-55% of their total IFN-gamma response to PfRBC, depletion of CD3(+) cells completely abrogated the ability of remaining PBMC, including NK cells, to produce IFN-gamma. Although NK responses to PfRBC were partially dependent on endogenous IL-2 signaling and could be augmented by exogenous IL-2 in whole PBMC populations, this factor alone was insufficient to rescue NK responses in the absence of T cells. Thus, NK cells make a significant contribution to total IFN-gamma production in response to PfRBC as a consequence of their dependency on (memory) T-cell help, with likely positive implications for malaria vaccine development.